Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease. Prior studies indicate a strong genetic component to the disease involving multiple loci. Present modes to initially detect the presence of AAA as well as determine which lesions are at risk for rapid growth/rupture are suboptimal. Thus, further advances in aneurysm care will require enhanced risk stratification tools. In our current Vascular SCCOR in AAA Disease at Stanford, we have employed a data-rich strategy to identify biologically relevant blood proteins that are informative in AAA disease. However, factors found in blood (secreted by AAA lesions) are unlikely to capture the breadth of the underlying pathophysiological processes. We propose to exploit the careful phenotyping of both cases and controls of the Abdominal Aortic Aneurysm-Simple Treatment or Prevention (AAA-STOP) trial to identify novel DNA sequence variants associated with AAA. We will take advantage of next-generation high-throughput sequencing technology to resequence candidate genes identified by our experimental strategy involving whole genome transcriptional profiling to build relevant expression networks. Novel missense variants will be replicated in a second subcohort of AAA-STOP as well as in a complementary cohort of equally well-phenotyped AAA patients and controls- participants of the Western Australia Screening Study (WASS). Finally, validated sequence variants will be combined with protein biomarker and clinical data to determine their additive value to disease algorithms of diagnosis and prognosis. In addition, identified rare missense variants are likely to add insight into the underlying biological processes regulating AAA formation as well as important gene-environment interactions. As such, we propose to pursue and complete the following Specific Aims: 1. to identify rare sequence variants associated with AAA disease in samples from the AAA-STOP cohort. 2. To perform validation genotyping in a second set of samples from AAA-STOP and a subcohort of the Western Australia Screening Study. To determine if rare sequence variants are predictive of disease progression and whether they add to phenotypic data, protein biomarker values, and interaction terms to produce useful diagnostic and prognostic algorithms for disease monitoring. This collaboration represents a unique opportunity to further leverage the ongoing success of the Stanford AAA SCCOR and WASS clinical trials into meaningful clinical guidelines for patients with a common and life threatening disease. In addition, rare variants will likely provide significant insight into disease pathobiology as well as guide disease management and future research. PUBLIC HEALTH RELEVANCE: Project Narrative Abdominal aortic aneurysm (AAA) is a common, morbid, and frequently lethal disease of older Americans. We propose to identify novel genetic factors that predispose individuals to develop AAA by deep sequencing of candidate genes in subjects enrolled in our NIH-sponsored clinical trial. In addition, we will determine if identified genetic markers add to known clinical parameters to help guide clinical care of AAAs. (End of Abstract)